Marine ladder polyethers, including gambierol, are the toxic constituents in many harmful algal blooms known as red tide events. These potent toxins can only be isolated in small quantities from their natural sources and the study of their biological activity could only be undertaken once their total synthesis was achieved. Unlike several other marine ladder polyethers which activate voltage-gated sodium ion channels, gambierol has been shown to inhibit voltage-gated potassium ion channels (Kv channels) in mouse taste cells. Kv channel blockers are potential therapeutic agents in the treatment of arrhythmia, diseases of the central nervous system, and as immunosuppressants. In addition, ladder polyethers and their derivatives have found use as molecular probes to elucidate the structure and function of voltage-gated ion channels, which ultimately leads to the improved design of therapeutic agents. The proposed total synthesis of the marine ladder polyether gambierol takes advantage of a directing group-free templated epoxide-opening cascade reaction that has the potential to streamline the synthesis of the toxin. The Jamison group has recently demonstrated the success of this method in simplified systems, but to date it has not been exploited in the total synthesis of a marine polyether. Improved access to the natural product and synthetic derivatives will enable further biological study and lead to a greater understanding of ion channel structure and function. The hallmark structural features of marine ladder polyethers include a series of syn/trans/syn fused cyclic ethers possessing C-C-O (carbon-carbon-oxygen) connectivity throughout the polyether framework, regardless of the intermediary ring size. One biosynthetic hypothesis that accounts for these structural features involves the epoxidation of a polyolefin, followed by an epoxide-opening cascade to form all of the ladder rings in a single step. The successful demonstration of an epoxide-opening cascade within the context of a total synthesis would additionally provide experimental support for this biosynthetic hypothesis. PUBLIC HEALTH RELEVANCE: Marine ladder polyether toxins are responsible for the neurotoxic effects resulting from the consumption of fish and shellfish during red tide events. One of these toxins, gambierol, has been shown to inhibit certain ion channels. A concise total synthesis of gambierol will provide sufficient quantities of the natural toxin and its synthetic derivatives to enable further biological study. An increased understanding of ion channel structure and function could lead to treatments for arrhythmia and disorders of the central nervous system.